Transplantation tolerance: lessons from experimental rodent models

Immunological tolerance or functional unresponsiveness to a transplant is arguably the only approach that is likely to provide long-term graft survival without the problems associated with life-long global immunosuppression. Over the past 50 years, rodent models have become an invaluable tool for elucidating the mechanisms of tolerance to alloantigens. Importantly, rodent models can be adapted to ensure that they reflect more accurately the immune status of human transplant recipients. More recently, the development of genetically modified mice has enabled specific insights into the cellular and molecular mechanisms that play a key role in both the induction and maintenance of tolerance to be obtained and more complex questions to be addressed. This review highlights strategies designed to induce alloantigen specific immunological unresponsiveness leading to transplantation tolerance that have been developed through the use of experimental models

Negative Feedback Regulation of T Cells via Interleukin-2 and FOXP3 Reciprocity

As interleukin-2 (IL2) is central to the clonal expansion of antigen-selected T cells, we investigated the relationship between IL2 and the negative regulatory transcription factor FOXP3. We found IL2 to be responsible for T cell antigen receptor (TCR)-activated FOXP3 expression by both CD4+ and CD8+ human T cells, and as anticipated, FOXP3 expression restricted TCR-stimulated IL2 expression. However, no evidence could be found that FOXP3+ cells actively suppress IL2 expression by FOXP3- cells. These data are consistent with an IL2/FOXP3-dependent negative feedback loop that normally regulates the T cell immune response. It follows that a defect in this negative feedback loop as a result of a deficiency of either IL2 or FOXP3 will lead to a hyperproliferative autoimmune syndrome, without the necessity of invoking an active suppressive function for FOXP3+ T cells

Special regulatory T cell review: How I became a T suppressor/regulatory cell maven

I have briefly reviewed the factors that motivated me to change my views about the existence and importance of suppressor/regulatory T cells and to devote the majority of my laboratory efforts to this newly revitalized area of immunologic research. I am optimistic that manipulation of regulatory T-cell function will shortly be applicable to the clinic

FOXP3+ regulatory T cells: Current controversies and future perspectives.

Regulatory T cells (Treg) provide protection from autoimmune disease, graft-versus-host disease, transplant rejection and overwhelming tissue destruction during infections. Conversely, high Treg numbers enable cancer cells to evade the host immune response. Thus, Treg are seen as an important tool to manipulate the immune response. However, as the immunological community is trying to move this knowledge from mice to humans, contradictory results regarding the number and function of Treg in various diseases are appearing. This problem arises because we cannot clearly define Treg populations on the basis of expression of CD25 and other cell surface markers in humans. This review addresses the utility of the FOXP3 forkhead transcription factor for the identification of Treg populations and summarizes recent data on the expression of FOXP3 in lymphomas. It is crucial to really understand Treg biology before attempting therapies, including (i) the injection of expanded Treg to cure autoimmune disease or prevent graft-versus-host disease or (ii) the depletion or inhibition of Treg in cancer therapy. For instance, new data arising from the study of haematological malignancies highlight the additional complexity of systems where malignant cell populations may also be direct Treg targets

Rapid suppression of cytokine transcription in human CD4⁺CD25ˉ T cells by CD4⁺Foxp3⁺ regulatory T cells: Independence of IL-2 consumption, TGF-β, and various inhibitors of TCR signaling.

CD4+CD25(high) forkhead box P3+ regulatory T cells (Treg) are critical mediators of peripheral self-tolerance and immune homeostasis. Treg suppress proliferation and cytokine production of conventional T cells (Tcon). The exact mechanism of suppression, however, is still unknown. To gain a better understanding of Treg function, we investigated the kinetics of cytokine suppression in Tcon reisolated from cocultures with preactivated human Treg. Treg inhibited induction of Th1 cytokine mRNA as early as 1 h after stimulation, whereas induction/suppression of Th2 cytokines was delayed to 10-15 h. We show that immediate cytokine mRNA suppression in Tcon was neither dependent on TGF-beta/IL-10 or IL-2 consumption, nor on induction of the transcriptional-repressor forkhead box P3 or other anergy-related genes (e.g., gene related to anergy, transducer of ErbB-2, forkhead homolog-4, repressor of GATA, inducible cAMP early repressor). In contrast, lymphocyte activation gene 3, suppressor of cytokine signaling 1, and suppressor of cytokine signaling 3 mRNA were strongly up-regulated in Tcon in the presence of Treg. However, protein analysis did not confirm a role for these proteins in early suppression. Thus, the identification of a fast inhibitory mechanism in Tcon induced by Treg constitutes an important step for future efforts to unravel the entire elusive suppressive mechanism

CD4(+)CD25(+) FOXP3(+) regulatory T cells from human thymus and cord blood suppress antigen-specific T cell responses

Activation of self-reactive T cells in healthy adults is prevented by the presence of autoantigen-specific CD4(+)CD25(+) regulatory T cells (CD25(+) T(reg)). To explore the functional development of autoantigen-reactive CD25(+) T(reg) in humans we investigated if thymic CD25(+) T(reg) from children aged 2 months to 11 years and cord blood CD25(+) T(reg) are able to suppress proliferation and cytokine production induced by specific antigens. While CD4(+)CD25(−) thymocytes proliferated in response to myelin oligodendrocyte glycoprotein (MOG), tetanus toxoid and beta-lactoglobulin, suppression of proliferation was not detected after the addition of thymic CD25(+) T(reg). However, CD25(+) T(reg) inhibited interferon (IFN)-γ production induced by MOG, which indicates that MOG-reactive CD25(+) T(reg) are present in the thymus. In contrast, cord blood CD25(+) T(reg) suppressed both proliferation and cytokine production induced by MOG. Both cord blood and thymic CD25(+) T(reg) expressed FOXP3 mRNA. However, FOXP3 expression was lower in cord blood than in thymic CD25(+) T cells. Further characterization of cord blood CD25(+) T cells revealed that FOXP3 was highly expressed by CD25(+)CD45RA(+) cells while CD25(+)CD45RA(−) cells contained twofold less FOXP3, which may explain the lower expression level of FOXP3 in cord blood CD25(+) T cells compared to thymic CD25(+) T cells. In conclusion, our data demonstrate that low numbers of MOG-reactive functional CD25(+) T(reg) are present in normal thymus, but that the suppressive ability of the cells is broader in cord blood. This suggests that the CD25(+) T(reg) may be further matured in the periphery after being exported from the thymus